Project Summary Glaucoma causes progressive damage and death of retinal ganglion cells (RGCs) resulting in blindness. The prevalence of the disease will rise to a projected 3 million Americans by 2020. Our long-term goal is to prevent RGC death in the early stages of glaucoma and preserve vision. The objective of this study is to identify dysfunctional RGCs and the risk of their death, together with the time window of opportunity for their recovery. Our central hypothesis is that RGCs undergo a stage of reversible dysfunction before dying, and that RGC dysfunction is modifiable in a critical period during which RGC electrical activity is responsive to artificial elevation/lowering of the intraocular pressure (IOP). Temporary IOP elevation with be obtained by means of head-down body posture; IOP lowering will be obtained by means of topical treatment. Our study will include 600 subjects with suspicion of glaucoma but with normal vision and visual field that will be longitudinally monitored over 4 years with state-of-the-art pattern electroretinogram (PERG), Spectral-domain Optical Coherence Tomography (SD-OCT), and other clinical measures. PERG losses result from reduced activity of viable RGCs as well as from lack of activity from dead/missing RGCs; OCT losses result from loss of RGC/axon tissue. Our specific aims will determine the risk of losing substantial RGC/axon tissue over 4 years based on baseline PERG susceptibility to head-down posture (aim1), baseline PERG abnormality (aim 2), and presence/absence of IOP-lowering treatment during follow up. Successful completion of our research will establish the notion that RGC death in glaucoma is preceded by a defined stage of modifiable RGC electrical activity, and that the risk of developing glaucoma can be predicted at baseline based on PERG. The outcome of our research will provide 1) the basis for new provocative tests of RGC functional susceptibility/reversibility using a non-invasive PERG method, 2) information needed for new methods to predict the risk of glaucoma development , 3) the time window for preventing it by timely treatment of high-risk individuals.